Apparatus for producing high yield cores for use in a microarray block, method for using same

ABSTRACT

A method for making a microarray block with a recipient block having at least one bore therein. A mold having a cylindrical bore with a cross-sectional shape approximating the cross-sectional shape of the at least one bore of the recipient block can be provided. The first end of the mold can have an opening that communicates with a cylindrical bore of the mold. A biological sample and a liquid carrier medium can be introduced through the opening and solidified in the mold to form a core. The core can be removed from the mold and at least a portion of the core can be inserted into the at least one bore of the recipient block. Related methods and assemblies are provided.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. provisional patent applicationSer. No. 62/426,195 filed Nov. 23, 2016, the entire content of which isincorporated herein by this reference.

FIELD OF THE INVENTION

The present invention relates to microarray blocks and, moreparticularly, to high yield microarray blocks.

BACKGROUND

A current microarray block typically contains a body formed from amaterial and having one or more “cores” arranged in a predeterminedpattern in a body. Current materials for forming the body includeparaffin wax, an agarose gel and a polymeric medium. The cores containmaterial to be analyzed, for example biological or chemical species. Thecores may also contain a solid matrix material in which the material tobe analyzed is contained.

Prior art methods for the production of cell microarray blocks consistmainly of directly punching a donor block or processing cells in agarosepellets and placing them directly into a recipient block (see FIG. 1).See, for example, Kononen J, Bubendorf L, Kallioniemi A, Barlund M,Schraml P, Leighton S, Torhorst J, Mihatsch M J, Sauter G, KallioniemiOP. “Tissue microarrays for high-throughput molecular profiling of tumorspecimens.” Nature Medicine, July 1998, 4(7): 844-847 and U.S. Pat. No.6,103,518. An instrument that embodies such technique is commonly usedto produce such cell microarray blocks. See, for example, Montgomery K,Zhao S, van de Rijn M, and Natkunam Y. “A Novel Method for Making‘Tissue’ Microarrays from Small Numbers of Suspension Cells.” ApplImmunohistochem Mol Morphol, March 2005; 13(1): 80-84 and Waterworth A,Hanby A, Speirs V. “A novel cell array technique for high-throughput,cell-based analysis.” In Vitro Cell Dev Biol Anim, 2005, 41: 185-187.Material to be analyzed that is located in the interstitial spacesbetween punches is commonly wasted. Further, the overall yield of theblock is often limited by the depth of the minimum-thickness sample thathas been punched.

Prior art methods of the production of microarray blocks also includehigh-yield approaches. See, for example, U.S. Pat. No. 8,911,682, theentire content of which is incorporated herein by this reference.

DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic, cross-sectional side view of one step of a priorart method of microarray construction wherein sample material isembedded in an embedding medium.

FIG. 1B is a schematic, cross-sectional side view of another step of aprior art method of microarray construction wherein a coring needle isinserted into the combined materials of FIG. 1A.

FIG. 1C is a schematic, cross-sectional side view of another step of aprior art method of microarray construction wherein a coring needle, nowcontaining a core, has been retracted from the materials of FIG. 1Aleaving a hole in the materials of FIG. 1A.

FIG. 1D is a schematic, cross-sectional side view of another step of aprior art method of microarray construction wherein a recipient blockwith wells is shown.

FIG. 1E is a schematic, cross-sectional side view of another step of aprior art method of microarray construction wherein the core of FIG. 1Chas been placed in one of the wells of the recipient well of FIG. 1D.

FIG. 1F is a schematic, cross-sectional side view of another step of aprior art method of microarray construction wherein a separate samplematerial is embedded in a medium.

FIG. 1G is a schematic, cross-sectional side view of another step of aprior art method of microarray construction wherein a coring needle hasbeen inserted into the combined materials of FIG. 1F.

FIG. 1H is a schematic, cross-sectional side view of another step of aprior art method of microarray construction wherein a coring needle, nowcontaining a core, has been retracted from the materials of FIG. 1Fleaving a hole in the materials of FIG. 1F.

FIG. 1I is a schematic, cross-sectional side view of another step of aprior art method of microarray construction wherein the core of FIG. 1Hhas been placed in another one of the wells of the recipient well ofFIG. 1D.

FIG. 1J is a schematic, cross-sectional side view of another step of aprior art method of microarray construction wherein the recipient blockof FIG. 1D has been filled with further cores of sample material.

FIG. 2A is a perspective view, with internal hidden lines shown asdashed, of one embodiment of the apparatus of the present invention forcreating of high-yield cores for a microarray block, more specifically aperspective view of one embodiment of a casting element and a containerelement of the present invention.

FIG. 2B is a side view, with internal hidden lines shown as dashed, ofthe casting element and container element of FIG. 2A shown prior toinsertion of the casting element into an end of the container element.

FIG. 2C is a side view, with internal hidden lines shown as dashed, ofthe casting element and container element of FIG. 2A shown afterinsertion of the casting element into the end of the container element,with no sealing element at the mating location of the casting elementwith the container element.

FIG. 3A is a perspective view, with internal hidden lines shown asdashed, of one embodiment of the apparatus of the present invention forcreating of high-yield cores for a microarray block, more specifically aperspective view of one embodiment of a casting element and a containerelement of the present invention, with one embodiment of a sealingelement at one end of the casting element.

FIG. 3B is a side view, with internal hidden lines shown as dashed, ofthe casting element and container element of FIG. 3A shown prior toinsertion of the casting element into an end of the container element.

FIG. 3C is a side view, with internal hidden lines shown as dashed, ofthe casting element and container element of FIG. 3A shown afterinsertion of the casting element into the end of the container element,the sealing element positioned at the interface of the casting elementand the container element.

FIG. 4A is a side view, with internal hidden lines shown as dashed, ofone embodiment of the apparatus of the present invention for creating ofhigh-yield cores for a microarray block, more specifically a side viewof one embodiment of a casting element and a container element of thepresent invention shown prior to insertion of the casting element intoan end of the container element.

FIG. 4B is a side view, with internal hidden lines shown as dashed, ofthe casting element and container element FIG. 4A shown after insertionof the casting element into the end of the container element, with nosealing element at the mating location of the casting element with thecontainer element. One embodiment of a plunger is attached to oneembodiment of a plunger rod, which passes through an aperture of thecontainer element.

FIG. 5A is a side view, with internal hidden lines shown as dashed, ofone embodiment of the apparatus of the present invention for creating ofhigh-yield cores for a microarray block, more specifically a side viewof one embodiment of a casting element and a container element of thepresent invention shown prior to insertion of the casting element intoan end of the container element.

FIG. 5B is a side view, with internal hidden lines shown as dashed, ofthe casting element and container element FIG. 5A shown after insertionof the casting element into the end of the container, with oneembodiment of a sealing element positioned at the interface of castingthe element and the container element. One embodiment of a plunger isattached to one embodiment of a plunger rod, which passes through anaperture of the container element.

FIG. 6A a perspective, top view of one embodiment of a long-aspect-ratiostraightening element of the present invention having a groove in thetop surface thereof. A lid may optionally be attached to the top surfaceto contain a core placed in the groove, for example during the processesillustrated in FIG. 7 or 8.

FIG. 6B a top view of the long-aspect-ratio straightening element ofFIG. 6A.

FIG. 6C an end view of the long-aspect-ratio straightening element ofFIG. 6A.

FIG. 7A is a schematic illustration of one step of one embodiment of amethod of the present invention for creating high-yield cores for amicroarray block wherein a liquid form of matrix material is dispensedfrom a pipette into a container to mix with cells in the container.

FIG. 7B is a schematic illustration of another step of one embodiment ofa method of the present invention for creating high-yield cores for amicroarray block wherein the liquid form of matrix material is mixedwith the cells to form a mixture in the container.

FIG. 7C is a schematic illustration of another step of one embodiment ofa method of the present invention for creating high-yield cores for amicroarray block wherein a casting member is contracted relative to thecontainer, for example the casting member is inserted into thecontainer.

FIG. 7D is a schematic illustration of another step of one embodiment ofa method of the present invention for creating high-yield cores for amicroarray block wherein the casting member and the container arefurther relatively contracted.

FIG. 7E is a schematic illustration of another step of one embodiment ofa method of the present invention for creating high-yield cores for amicroarray block wherein casting member and the container are furtherrelatively contracted, for example the casting member is furtherinserted into the container in order to propel or move the mixture fromthe container into a lumenal volume of the casting member to form acolumn of the mixture in the casting member.

FIG. 7F is a schematic illustration of another step of one embodiment ofa method of the present invention for creating high-yield cores for amicroarray block wherein the casting member containing the column of themixture has been removed from the container. The matrix materialcontained in mixture may become solid or semi-solid during or betweenthe steps of FIGS. 7E and 7F.

FIG. 7G is a schematic illustration of another step of one embodiment ofa method of the present invention for creating high-yield cores for amicroarray block wherein the column of mixture is being transferred fromthe casting member to a straightening element, for example thestraightening element of FIGS. 6A-6C.

FIG. 7H is a schematic illustration of another step of one embodiment ofa method of the present invention for creating high-yield cores for amicroarray block wherein the column of mixture is made compatible with asubsequent embedding and/or sectioning process, for example whiledisposed in the straightening element.

FIG. 7I is a schematic illustration of another step of one embodiment ofa method of the present invention for creating high-yield cores for amicroarray block wherein a segment of a solidified core is inserted intoa well of a recipient block.

FIG. 7J is a schematic illustration of another step of one embodiment ofa method of the present invention for creating high-yield cores for amicroarray block wherein a microarray block has been completed byfilling all of the desired wells of the recipient block with solidifiedcores of the mixture.

FIG. 8A is a schematic illustration of one step of one embodiment of amethod of the present invention for creating high-yield cores for amicroarray block wherein a liquid form of matrix material is dispensedfrom a pipette into a container to mix with cells in the container.

FIG. 8B is a schematic illustration of one step of one embodiment of amethod of the present invention for creating high-yield cores for amicroarray block wherein the liquid form of matrix material is mixedwith the cells to form a mixture in the container.

FIG. 8C is a schematic illustration of one step of one embodiment of amethod of the present invention for creating high-yield cores for amicroarray block wherein a casting member is contracted relative to thecontainer, for example the casting member is inserted into the container

FIG. 8D is a schematic illustration of one step of one embodiment of amethod of the present invention for creating high-yield cores for amicroarray block wherein a plunger is advanced with respect to thecontainer to move the mixture in the container closer to the castingmember.

FIG. 8E is a schematic illustration of one step of one embodiment of amethod of the present invention for creating high-yield cores for amicroarray block wherein the plunger is further advanced with respect tothe container in order to propel or move the mixture from the containerinto the lumenal volume of the casting member to form a column of themixture in the casting member.

FIG. 8F is a schematic illustration of another step of one embodiment ofa method of the present invention for creating high-yield cores for amicroarray block wherein the casting member containing the column of themixture has been removed from the container. The matrix materialcontained in mixture may become solid or semi-solid during or betweenthe steps of FIGS. 8E and 8F.

FIG. 8G is a schematic illustration of another step of one embodiment ofa method of the present invention for creating high-yield cores for amicroarray block wherein the column of mixture is being transferred fromthe casting member to a straightening element, for example thestraightening element of FIGS. 6A-6C.

FIG. 8H is a schematic illustration of another step of one embodiment ofa method of the present invention for creating high-yield cores for amicroarray block wherein the column of mixture is made compatible with asubsequent embedding and/or sectioning process, for example whiledisposed in the straightening element.

FIG. 8I is a schematic illustration of another step of one embodiment ofa method of the present invention for creating high-yield cores for amicroarray block wherein a segment of a solidified core is inserted intoa well of a recipient block.

FIG. 8J is a schematic illustration of another step of one embodiment ofa method of the present invention for creating high-yield cores for amicroarray block wherein a microarray block has been completed byfilling all of the desired wells of the recipient block with solidifiedcores of the mixture.

FIG. 9A is a schematic illustration of one step of one embodiment of amethod of the present invention, with internal hidden lines shown asdashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein an end of thecasting element has been inserted into an end of the container element,with no sealing element at the interface between the casting element andthe container element.

FIG. 9B is a schematic illustration of another step of one embodiment ofa method of the present invention, with internal hidden lines shown asdashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein the castingelement has been advanced to the point of contact with the mixture inthe container element.

FIG. 9C is a schematic illustration of another step of one embodiment ofa method of the present invention, with internal hidden lines shown asdashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein the castingelement has been advanced to a position where the mixture in thecontainer element has been partially transferred from a reservoir in thecontainer element to a duct of the casting member.

FIG. 9D is a schematic illustration of another step of one embodiment ofa method of the present invention, with internal hidden lines shown asdashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein the castingelement has been advanced to a position where the mixture has been fullyor nearly fully transferred from the reservoir in the container elementto the duct of casting member.

FIG. 10A is a schematic illustration of one step of one embodiment of amethod of the present invention, with internal hidden lines shown asdashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein an end of thecasting element has been inserted into an end of the container element,with a sealing element at the interface between the casting element andthe container element.

FIG. 10B is a schematic illustration of another step of one embodimentof a method of the present invention, with internal hidden lines shownas dashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein the castingelement has been advanced to the point of contact with the mixture inthe container element.

FIG. 10C is a schematic illustration of another step of one embodimentof a method of the present invention, with internal hidden lines shownas dashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein the castingelement has been advanced to a position where the mixture in thecontainer element has been partially transferred from a reservoir in thecontainer element to a duct of the casting member.

FIG. 10D is a schematic illustration of another step of one embodimentof a method of the present invention, with internal hidden lines shownas dashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein the castingelement has been advanced to a position where the mixture has been fullyor nearly fully transferred from the reservoir in the container elementto the duct of casting member.

FIG. 11A is a schematic illustration of one step of one embodiment of amethod of the present invention, with internal hidden lines shown asdashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein an end of thecasting element has been inserted into an end of the container element,with no sealing element at the interface between the casting element andthe container element.

FIG. 11B is a schematic illustration of another step of one embodimentof a method of the present invention, with internal hidden lines shownas dashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein a plunger of theinvention, for example carried by the container element, has beenadvanced so that the mixture in the container element is in contact withan end of the casting element.

FIG. 11C is a schematic illustration of another step of one embodimentof a method of the present invention, with internal hidden lines shownas dashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein the plunger hasbeen advanced to a position where the mixture in the container elementhas been partially transferred from a reservoir in the container elementto a duct of the casting member.

FIG. 11D is a schematic illustration of another step of one embodimentof a method of the present invention, with internal hidden lines shownas dashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein the plunger hasbeen advanced to a position where the mixture has been fully or nearlyfully transferred from the reservoir in the container element to theduct of the casting member.

FIG. 12A is a schematic illustration of one step of one embodiment of amethod of the present invention, with internal hidden lines shown asdashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein an end of thecasting element has been inserted into an end of the container element,with a sealing element at the interface between the casting element andthe container element.

FIG. 12B is a schematic illustration of another step of one embodimentof a method of the present invention, with internal hidden lines shownas dashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein a plunger of theinvention, for example carried by the container element, has beenadvanced so that the mixture in the container element is in contact withan end of the casting element.

FIG. 12C is a schematic illustration of another step of one embodimentof a method of the present invention, with internal hidden lines shownas dashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein the plunger hasbeen advanced to a position where the mixture in the container elementhas been partially transferred from a reservoir in the container elementto a duct of the casting member.

FIG. 12D is a schematic illustration of another step of one embodimentof a method of the present invention, with internal hidden lines shownas dashed, for transferring a mixture from one embodiment of a containerelement of the present invention to the lumenal volume of one embodimentof a casting element of the present invention wherein the plunger hasbeen advanced to a position where the mixture has been fully or nearlyfully transferred from the reservoir in the container element to theduct of the casting member.

FIG. 13 is a perspective view of one embodiment of a microarrayrecipient block of the present invention, with wells formed therein,together with a histologic cassette.

FIG. 14 is a top view of the microarray recipient block and histologiccassette of FIG. 13.

FIG. 15 is a perspective view, from an opposite angle, of the microarrayrecipient block and histologic cassette of FIG. 13.

FIG. 16 is a front view, with hidden lines shown dashed, of themicroarray recipient block and histologic cassette of FIG. 15.

FIG. 17 is a side view, with hidden lines shown dashed, of themicroarray recipient block and histologic cassette of FIG. 15.

FIG. 18 is a cross-sectional view, taken along the line 18-18 of FIG.16, of the microarray recipient and histologic cassette block of FIG.15, showing the wells of the recipient block, the interlocked connectionof the recipient block with the histologic cassette, and the optionalthrough-holes of the recipient block.

FIG. 19 is an enlarged side cross-sectional view, similar to the sidecross-sectional view of FIG. 18, of the microarray recipient block andhistologic cassette of FIG. 15.

FIG. 20 is an exploded perspective view of one embodiment of acasting-mold system for creating a recipient block and histologiccassette assembly, for example similar to the microarray recipient blockand histologic cassette assembly of FIG. 13, and includes a mold, thehistologic cassette and an optional mold insert.

FIG. 21 is a front view, with hidden lines shown dashed, of thecasting-mold system of FIG. 20.

FIG. 22 is a side view, with hidden lines shown dashed, of thecasting-mold system of FIG. 20.

FIG. 23 is a cross-sectional view, taken along the line 23-23 of FIG.21, of the casting mold system of FIG. 20.

FIG. 24 is an assembled perspective view of the casting mold system ofFIG. 20.

FIG. 25 is a top plan view of the assembled casting mold system of FIG.24.

FIG. 26 is a cross-sectional view, taken along the line 26-26 of FIG.27, of the assembled casting mold system of FIG. 24.

FIG. 27 is a side view, with hidden lines shown dashed, of the assembledcasting mold system of FIG. 24.

FIG. 28 is a rear view, with hidden lines shown dashed, of the assembledcasting mold system of FIG. 24.

FIG. 29 is a cross-sectional view, taken along the line 29-29 of FIG.28, of the assembled casting mold system of FIG. 24.

FIG. 30 is a top plan view of another embodiment of an assembledcasting-mold system for creating a recipient block and histologiccassette assembly, for example similar to the microarray recipient blockand histologic cassette assembly of FIG. 13.

FIG. 31 is a side view, with hidden lines shown dashed, of the assembledcasting mold system of FIG. 30.

FIG. 32 is front view, with hidden lines shown dashed, of the assembledcasting mold system of FIG. 30.

FIG. 33 is a cross-sectional view, taken along the line 33-33 of FIG.31, of the assembled casting mold system of FIG. 30.

FIG. 34 is a schematic illustration of one step of one embodiment of amethod of the present invention, with internal hidden lines shown asdashed, for creating a recipient block and histologic cassette assemblyof the present invention, for example the recipient block and histologiccassette assembly of FIG. 13, by for example pouring a liquid into thecasting mold system of FIG. 24 or FIG. 30.

FIG. 35 is a schematic illustration of another step of one embodiment ofa method of the present invention, with internal hidden lines shown asdashed, for creating a recipient block and histologic cassette assemblyof the present invention, for example the recipient block and histologiccassette assembly of FIG. 13, wherein a liquid has been poured into thecasting mold system of FIG. 24 or FIG. 30.

DETAILED DESCRIPTION

In any embodiment of the invention, an apparatus and method can beprovided for forming cores containing a sample material, for example foruse in a microarray block. In any embodiment, the apparatus can includea container for holding the sample material and a liquid matrix materialand a tubular casting member for cooperatively engaging the containerand receiving the sample material and the liquid matrix material fromthe container and forming a core of the sample material and matrixmaterial. In any embodiment, the core can be a high-density core of thesame material and the matrix material. In any embodiment, the samplematerial can be a biological material, for example tissue sample or cellcultures.

Any suitable ratio of sample material to liquid matrix material can beutilized. Ratios of sample material to liquid matrix material rangingfrom 1:100 to 100:1 can be utilized and provided. Ratios of samplematerial to liquid matrix material ranging from 1:3 to 3:1 can beutilized and provided. In this regard, where relatively few cells arerequired for a diagnosis, a corresponding low ratio of sample materialto liquid matrix material can be utilized. For example, ratios in therange of approximating 1:100, for example in the case of disaggregatedcells, may generate cell counts on the order of 100 in sections of acore diameter of two millimeters, which may be sufficient for someimmune-histochemical diagnosis, for example. In certain instances, verydense sample material may be required. For example, a ratio of samplematerial to liquid matrix material of 100:1 could yield a nearly fullydense core of sample.

The embodiments of the invention set forth below are examples of theinvention, and may in some instances be broader than the foregoingembodiment of the invention but are not intended to limit the breadth ofthe foregoing embodiment or the breadth of the invention. Additionalfeatures of the invention set forth in such embodiments are optional. Afeature of any embodiment set forth below can be combined with theforegoing embodiment, with or without any other feature of anyembodiment set forth below. All characteristics, steps, parameters andfeatures of any method, process, apparatus, device or system describedbelow are not limited to any specific embodiments set forth below, butinstead are equally applicable to the foregoing embodiment of theinvention and to all embodiments of the invention. Broad terms anddescriptors are replaced in some instances with more specific terms anddescriptors, not to limit a disclosure to a specific term or descriptorbut merely for ease of discussion and understanding.

The apparatus or assembly of the invention can be of any suitable type,and in any embodiment, for example as illustrated in FIGS. 2-5, thecontainer, for example container 14 or 20, can be a container member orelement 13. The container element can have a cylindrical exterior or anexterior surface of any other suitable shape. The container element canbe a cylindrical element 13. The container element 13 can have areservoir therein, for example reservoir 15, for holding the mixture ofsample material and the matrix material, for example matrix material 16.The container can be of any suitable solid material such as glass,plastic, metal, ceramic, or elastomer. The container element 13 can betubular and be provided with opposite first and second ends 31, 32. Inany embodiment, for example container 14, the first end 31 of thetubular container can be open, that can be provided with an opening 33,and the opposite second end 32 of the container can be closed. Thereservoir can be of any suitable size or shape and in any embodiment canbe a cylindrical bore 15 extending between the first and second ends ofthe tubular container. The opening 33 in the first end of the containercan have a cross section that can be the same as the cross section ofthe cylindrical bore 15. In any embodiment, the bore 15 can have acircular cross section. In any embodiment, the container, for examplecontainer 14 or 20, can be capable of withstanding centrifugation.

In any embodiment, for example container 20, the second end 32 of thecontainer or cylindrical member or element, for example containerelement 13, can have an opening or aperture 26 therein, for example acentral aperture. In any embodiment, the container can include aplunging element or plunger 22 for moving the sample material and matrixmaterial towards the opening 33 in the first end 31 of the containerelement 13. The plunging element can have a cross section approximatingthe internal cross section of the reservoir or cylindrical bore 15 ofthe container, for example to minimize sample material or matrixmaterial extending between the plunger 22 and the internal surface 36 ofthe container. An urging or propulsion means or an urging or propulsionmechanism can be coupled to or carried by the container for exerting aforce on the plunger so as to advance the plunger towards the opening inthe first end of the container. The urging means or mechanism can be ofany suitable type, such as a source of pressurized fluid coupled to theaperture 26 in the second end 32 of the container or a rod or post 24coupled to the plunger 22 and extending through the aperture 26.

The tubular casting member 10 of the apparatus or assembly of theinvention can be referred to as a second container or mold for formingthe high-density core, which can be a high density cylindrical core. Thetubular casting member can be referred to or described as a tubularcasting element, an elongate member, a cylindrical member, a tubularmember or a tube, and can be provided with opposite first and secondends 41, 42. The tubular casting member can be of any suitable solidmaterial such as glass, plastic, metal, ceramic, or elastomer. In anyembodiment, both the first end 41 and the second end 42 of the tubularcasting member can be open. The tubular casting member can be of anysuitable size or shape and in any embodiment can be a cylinder having anexternal cross section approximating the internal cross section of thecontainer element 13 of the container. For example, the tubular castingmember can have an external circular cross section. In any embodiment,the tubular casting member can have an external transverse dimension,such as an external diameter, that can be slightly less than theinternal transverse dimension, such as internal diameter, of thecontainer. In any embodiment, the first end 41 of the tubular castingmember can slidably extend through the opening 33 in the first end 31 ofthe container element 13 of the container and through the cylindricalbore 15 of the container. For example, the outside or external surface43 of the tubular casting member can slidably and sealably engage theinside or internal surface 36 of the bore 15 of the container. In thismanner, the tubular casting member 10 and the container can movelongitudinally relative to each other from an extended configuration toa contracted configuration. Certain extended configurations of theassembly or apparatus of the invention are illustrated in the first sideviews of FIGS. 2-5 and certain contracted configurations of the assemblyor apparatus of the invention are illustrated in the second side viewsof FIGS. 2-5.

In any embodiment, a suitable sealing element or seal, for example seal18, can be provided around the first end 41 of the tubular castingmember 10, within the tubular bore 15 of the container element 13 of thecontainer for example at the first end 31 of the container or both forenhancing a fluid-tight seal between the outside of the tubular castingmember 10 and the inside of the bore of the container, including duringslidable movement of the tubular casting member relative to thecontainer (see FIGS. 3 and 5). The seal can be made from any suitablematerial, such as a silicone or other elastomeric material.

In any embodiment, the seal between casting element 10 and containerelement 13 need not involve insertion. For example, such a seal may beachieved via contact between the faces at the tips of end 41 of castingelement and end 31 of container element, respectively, with or without asealing element such as a gasket at the interface.

The internal surface of the casting member 10 can form a channel or duct12 with a given size and shape. The cross-sectional size and shape ofthe internal surface may be constant throughout the length of thecasting member, for example a cylinder, and in any embodiment can be acircular cylinder. The duct or bore 12 within the casting member cancommunicate with a first opening 51 at the first end 41 of the castingmember and a second opening 52 at the second end 42 of the castingmember.

Another structure of the present invention is a long-aspect-ratiocassette or other straightening element (see FIG. 6) that contains andsupports the core after it is removed from the casting member. Thestraightening element can be of any suitable type. In any embodiment, astraightening element or device 101 can be provided formed from anelongate support structure 102 made from any suitable material such as arigid or flexible plastic, ceramic, metal or elastomer. Thestraightening element can be referred to as a cassette. The structure102 can have a bottom surface 103, that can be planar, and a top surface104 provided with an elongate groove or channel 106 formed therein. Inany embodiment, the channel 106 can have a length at least equal to thecore of the sample material and a transverse dimension at least equal tothe width or transverse dimension of the core.

One method of forming a microarray block of the invention, for example acell microarray block, is illustrated schematically in FIGS. 7-8. Themethod of FIG. 7 can utilize any suitable container and casting member,such as container 14 and casting member 10. The method of FIG. 8 canutilize any suitable container and casting member, such as container 20and casting member 10. In step 300, pipette(s) or other suitabledispenser(s) 304 can be used to place a combination of cells 306 and theliquid form of a suitable matrix material 307 into the container 302,for example containers 14 or 20. In any embodiment, the cells and liquidcan form of the matrix material may be mixed prior to placing it intothe container. In the method of FIG. 8, a plunging element 308 existswithin the container, for example plunging element 22. Step 310 depictsthe mixture 312 of cells and liquid form of the matrix material in thecontainer. In step 320, the casting member 322, for example castingmember 10, is shown upon insertion into an open end of the container. Inthese diagrams, a sealing element 324, for example seal 18, can beprovided to facilitate a fluid-tight seal between the casting elementand the container. In any embodiment, a sufficient seal may be achievedwithout the use of such a sealing element. In step 330, one element canbe advanced toward another in such a way as to bring the surface of thefluid mixture 312 into contact with the casting element 322. In theembodiment of FIG. 7, said contact can be achieved by advancing thecasting element with respect to the container. In the embodiment of FIG.8, said contact can be achieved by advancing the plunging element 308with respect to the casting element. In step 340, the respectiverelative contraction of the container and casting member, for examplethe insertion of the casting member into the container, are continued tosuch an extent as to propel or transfer the mixture 312 into the lumenof the casting element, resulting in a column 342 of the mixture ofcells and liquid matrix, which can be referred to as a cylinder,assuming the shape of the lumen, channel, duct or bore of the castingelement. Subsequently, column 342 can be allowed to solidify, forexample by means of cooling or other mechanism, causing solidificationof the matrix material. Subsequent to solidification of column 342, thecasting element may be removed from contact with the container asdepicted in step 350. This step is optional, as the system may bedesigned to enable step 360 and/or 370 without said removal of contactbetween casting element and container. In step 360, the solid core canbe removed from the casting element after solidification. As depicted,depending upon the mechanical properties of the solidified matrixmaterial, the core may be highly flexible. In any embodiment, aspecialized straightening element 362, for example straightening element101 illustrated in FIG. 6, can receive the solidified core in step 360.The use of said straightening element is optional in the method.

In step 370, the solidified core can be made compatible with theembedding material, for example item or recipient block 386 in step 380,of the final microarray block. The recipient block can be made from anysuitable material including paraffin wax, an agarose gel and a polymericmedium. As used herein, the term made compatible can represent theestablishment of properties in a material pair (core and embeddingmaterial) between which a bond may be formed with sufficient strength toenable sections of the block to be cut which have physical integrity. Inany embodiment where the embedding material of the block 386 can beparaffin and the core's matrix material can be agarose gel, step 370 mayinvolve dehydration followed by paraffin infiltration of the agarosegel. The device represented by item 372 in step 370 may be a standard“tissue processing” instrument from the histology industry. The resultof step 370 can be the core 382 having been made compatible with theembedding material of block 386.

Step 380 shows, in sectional side view, a segment from the core 382being placed into an existing recipient block 386 mounted on ahistologic cassette 388. The segment created by parting the core alongthe line 384, can be formed by any suitable means, for example using ascalpel or other blade. The segment can be formed either before or afterits placement in the respective bore of the recipient block. Step 390shows, in top view, a resulting microarray block. A suitable bondingstep, for example a heating step, may be incorporated after step 380 inorder to enhance the bond between the recipient block and the coresplaced therein. In any embodiment, other steps such as polymerization ofthe embedding medium may be incorporated after step 380 in order toenhance the bond between the recipient block and the cores. Apolymerization step may be desirable, for example, where the recipientblock can be formed from a polymeric medium. Other methods may be usedfor embedding or disposing the cores within the embedding material, forexample molding or otherwise forming a block around the cores. In anyembodiment, for example, the cores may be held in a desiredconfiguration within a mold and a liquid form of the embedding materialcan be introduced into the mold and allowed to solidify.

The progression of steps 320 through 340 in FIG. 7 are depicted in onemethod of the invention utilizing container 14 and casting member 10 inFIGS. 9 and 10, respectively for the embodiments without and with asealing element between the casting element and the container. Theprogression of steps 320 through 340 in FIG. 8 are depicted in onemethod of the invention utilizing container 20 and casting member 10 inFIGS. 11 and 12, respectively for the embodiments without and with asealing element between the casting element and the container. FIGS. 11and 12 depict an embodiment in which the plunger element can be advancedby means of a rod, for example rod 24, passing through an aperture, forexample aperture 26, provided at the second end 32 of the containerelement 13. It is appreciated that other means may be used to applyforce to advance the plunger element, for example plunger 22. Forexample, pressurized gas or liquid may be introduced through theaperture 22 shown so as to urge the plunger from a first or homeposition located nearby end 32 to a second or actuated position awayfrom end 32, for example closer to end 31. In any embodiment, aferromagnetic material, or a magnetized material, may be coupled bydirect or indirect contact with the plunger element 22. In this case,for example, an urging force may be applied to the plunger element viathe application of a magnetic field, with or without the necessity of anaperture 26. In any embodiment, a magnetic element providing such urgingforce can be disposed outside of chamber or reservoir 15, that isoutside of container element 13.

FIGS. 13-19 depict an embodiment of a recipient block for use inconstructing a microarray block. The recipient block 201 can be bondedto a histologic cassette of any suitable type, for example cassette 388.Any embodiment of a suitable histologic cassette 202 can be formed froma body 203 made from any suitable material, such as rigid plastic. Body203 can include a planar support layer 204 having opposite first andsecond surfaces 206, 207, each of which can be planar. The body 203 canbe provided with a cavity 205, having a base formed by second surface207 of the planar support layer 204. The planar support layer can beprovided with a plurality of openings 208 extending between the firstand second surfaces 206, 207 for forming a plurality of support elements209 in the planar support layer 204. In any embodiment, each of theopenings 208 can be a slot, and in any embodiment each of the slots canextend parallel to each other. The recipient block 201 can be carried bythe cassette 202 in any suitable manner, for example supported by planarsupport layer 204. In any embodiment, the recipient block 201 can reston first surface 206 of the cassette 202. The recipient block 201 can besecured to the cassette, for example planar support layer 204 of thecassette 202, in any suitable manner. In any embodiment, a portion ofthe recipient block 201 can be embedded in at least a portion of theplanar support layer 204 so as to be carried by and secured to theplanar support layer 204 thereby.

Recipient block 201 can be formed from any suitable material, includingany of the materials disclosed herein. In any embodiment, the recipientblock can be formed from an agarose gel. In any embodiment, for examplewhere a portion of the recipient block can be embedded in the planarsupport layer 204, the recipient block 201 can have a first portion 211extending from the first surface 206 of the planar support layer 204 anda second portion 212 extending from the second surface 207 of the planarsupport layer 204. In any embodiment, the second portion 212 can bedisposed in cavity 205 of the cassette body 203. The recipient block 201can extend through at least some of the openings 208 in the planarsupport layer 204 so as to embed at least some of the support elements209 of the support layer 204 between the first and second portions 211,212 of the recipient block 201. The first portion 211 of the recipientblock 201 can have a surface 216, for example a top or front surface,spaced from the first surface 206 of the planar support layer 204. Inany embodiment, the surface 216 of the first portion 211 can be planarand parallel to the planar support layer 204. The first portion 211 ofthe recipient block can be provided with at least one bore or well 221extending into the first portion from the surface 216 that is adapted toreceive the biological sample material, for example a core of thebiological sample material and medium. In any embodiment, the firstportion 211 can include a plurality of parallel bores or wells 221extending from surface 216 into the first portion. The plurality ofbores 221 can be parallel to each other, and spaced in an array onsurface 216 with rows and columns of bores 221. One or more of the bores221 in the recipient block 201 can extend through the first portion 211and through one of the openings 208 in the planar support layer 204 andthrough the second portion 212. One or more of the bores 221 can have afirst section 222 in the first portion 211 with a transverse dimensionand a second section 223 in the second portion 211 with a transversedimension that can be smaller than the transverse dimension of the firstsection 222 of the bore 221. The first section 222 of the bore 221 canbe referred to as a well and the second section 223 of the bore 221 canbe referred to as a duct. The second portion 212 of the recipient block201 can have a surface 226, for example a top or front surface, spacedfrom the second surface 207 of the planar support layer 204. In anyembodiment, the surface 226 of the second portion 212 can be planar andparallel to the planar support layer 204.

FIGS. 20-33 depict an embodiment of a suitable casting system 499 forproducing recipient microarray blocks, for example recipient block 201.Item 500 is an optional component and can be a frame to occupy part ofthe hollow cavity 205 at the back of histologic cassette 510, forexample cassette 202. In any embodiment, item 500 can include a mold 502to form the second portion 212 of the recipient block 201. Item 520 caninclude a mold with an internal cavity 501 of the overall shape desiredfor the recipient block 201, for example the shape of the first portion211 of the recipient block 201. In any embodiment, item 520 can includea recess 503 for receiving cassette 510, which can include item 500disposed in the cavity 205 of the cassette 510.

FIG. 34 illustrates the pouring of a liquid into such a casting system,for example casting system 499. As indicated in FIG. 35, the pouredliquid can flow through the openings 208 in the histologic cassette 510and fills the volume on both sides of the cassette not occupied by items500 nor 520, for example cavity 501 in item 520 and cavity 502 in item500. The liquid material subsequently solidifies in any suitable manner,for example due to cooling or another mechanism such as a polymerizationreaction. The solid block material in FIG. 35, for example thesolidified material, can then be removed from the casting system,resulting in a recipient block 201 such as shown in FIGS. 13-19 butpossibly without bores yet formed in the block. The recipient block 201can be attached to the cassette 510 by interlocking through the openings208 in the cassette and around support elements 209 of the planarsupport layer 204 of the cassette.

One or more bores 221 of the recipient block 201, for example shown inFIGS. 13-19, can be formed in any embodiment by a material removalprocess such as drilling, punching, coring, or milling of the recipientblock 201. Alternatively, the one or more bores 221 can be formed in thecasting process, for example by using pins 530 as shown in FIGS. 32-33.Pins 530 may have additional protrusions (not shown in FIGS. 32-33) ofsmaller dimension that extend through openings 208 in the cassette 510in order to produce through-ducts in a portion of the recipient block201, for example ducts 223 in the second portion 212 of the recipientblock 201. Such ducts 223 can facilitate placement of the cores ofbiological material and medium within first section 222 of the one ormore bores 221 of the recipient block 201.

The wells in the recipient block, for example wells 222, andcorrespondingly the cores of the microarray, may be of any suitablesize. For example, such wells and cores may be cylindrical shapes havinga diameter ranging from 0.5 to 5 millimeters and a length ranging fromone to twenty millimeters.

In any embodiment, the material of the recipient block can be an agarosegel material, composed for example of 2% by volume agarose. During thecasting process, for example the process depicted in FIGS. 34-35, theliquid material may be the aqueous form of this agarose gel material, inwhich the remaining volume can be largely composed of water. In thisembodiment, after removal from the casting system 499 the block 201 withattached cassette 510 or 202 may be dehydrated and paraffin infiltrated,for the purpose of making it wettable by, and bondable with,paraffin-containing microarray cores.

In any embodiment of constructing a microarray block using recipientblock 201, step 380 from FIGS. 7-8 can be performed. In this step, cores382 can be placed in the wells 222 of the recipient block 201. A furtherstep may be performed to enhance the bonding of the cores to therecipient block. This step may comprise heating the combination ofrecipient block and cores to a temperature at which some fusing of thesematerials occurs, for example by softening or partial melting ofparaffin contained within one or more of these materials. In anyembodiment, the bonding step may include the addition of further liquidparaffin or other material. In any embodiment, the entire recipientblock 201 may be embedded in such a material by casting the liquid formof the material into another mold of volume larger equal to or largerthan the recipient block 201, then allowing the combination of allmaterials to become solid by cooling or another solidification mechanismsuch as a polymerization reaction.

In any embodiment, the recipient block 201 can be composed of a materialwhich remains solid or semi-solid when subjected to a temperature atwhich another substance, capable of bonding the cores to the recipientblock, exists in the liquid state. This property of such material of therecipient block 201 enables the liquid form of such other substance tobe added to the assembly of recipient block and cores while the relativepositions of the recipient block, cores, and histologic cassette aremaintained. In any embodiment, the material of the recipient block 201may be agarose gel that has been dehydrated and paraffin infiltrated,and the material used for bonding the cores to the recipient block maybe paraffin. In such embodiment, the agarose gel remains solid at thetemperature at which paraffin is liquid.

As used herein, a cylinder is intended to mean a surface traced by astraight line moving parallel to a fixed straight line and intersectinga fixed planar closed curve, a solid or surface bounded by a cylinderand two parallel planes cutting all its elements, or any combination ofthe foregoing.

In one aspect of the invention, a method for making a microarray blockcan be provided and can include providing a recipient block with atleast one bore therein, the at least one bore having a cross sectionalshape, providing a mold having a cylindrical bore with a cross sectionalshape approximating the cross sectional shape of the at least one boreof the recipient block, the mold having opposite first and second ends,the first end of the mold having an opening that communicates with thecylindrical bore of the mold, introducing a biological sample and aliquid carrier medium through the opening, solidifying the biologicalsample and the liquid carrier medium in the mold to form a core,removing the core from the mold and inserting at least a portion of thecore into the at least one bore of the recipient block.

The biological sample can be selected from the group consisting of atissue sample, cell cultures, disaggregated tissue, derivativebiological materials and a combination of the foregoing. The liquidcarrier medium can be selected from the group consisting of paraffinwax, agarose gel and a polymeric medium. The method can further includethe step of mixing the biological sample and the liquid carrier mediumwithin the cylindrical bore of the mold. The method can further includethe step of mixing the biological sample and the liquid carrier mediumbefore the introducing step. The solidifying step can include heatingthe biological sample and the liquid carrier medium in the mold. The atleast one bore in the recipient block can have a length and the core canhave a length independent of the length of the at least one bore. Thecore can have a length longer than the length of the at least one bore.The recipient block can be formed from a material, further comprisingthe step of making the core compatible with the material of therecipient block. The recipient block can be formed from paraffin and themaking the core compatible step can include dehydrating the core andinfiltrating the core with paraffin.

In one aspect of the invention, a method for making a microarray blockcan be provided and can include providing a mold having a cylindricalbore, the mold having opposite first and second ends, the first end ofthe mold having an opening that communicates with the cylindrical bore,introducing a biological sample and a liquid carrier medium through theopening in the mold, solidifying the biological sample and the liquidcarrier medium in the mold to form a core, removing the core from themold and disposing the core in a recipient block.

The disposing step can include forming a recipient block around at leasta portion of the length of the core. The disposing step can includeproviding a recipient block with at least one bore therein and insertingat least a portion of the core into the at least one bore of therecipient block.

In one aspect of the invention, a method for making a microarray blockcan be provided and can include providing a recipient block formed of amaterial and having at least one bore therein, the at least one borehaving a cross sectional shape, providing a core of a biological sampleand a carrier medium having a cross sectional shape approximating thecross sectional shape of the at least one bore of the recipient block,making the core compatible with the material of the recipient block andinserting at least a portion of the core into the at least one bore ofthe recipient block.

The recipient block can be formed from paraffin and the making the corecompatible step can include dehydrating the core and infiltrating thecore with paraffin. The at least one bore in the recipient block canhave a length and the core can have a length independent of the lengthof the at least one bore. The core can have a length longer than thelength of the at least one bore.

In one aspect of the invention, a method for making a microarray blockcan be provided and can include providing a cylindrical core of abiological sample and a carrier medium, disposing the core in arecipient block formed from a material and making the core compatiblewith the material of the recipient block before the disposing step.

The disposing step can include forming a recipient block around at leasta portion of the length of the cylindrical core. The disposing step caninclude providing a recipient block with at least one bore therein, thecylindrical core having a cross sectional shape approximating thecross-sectional shape of the at least one bore of the recipient block,and inserting at least a portion of the core into the at least one boreof the recipient block.

In one aspect of the invention, an assembly for forming a core of abiological sample for use in a recipient block having at least one borewith a cross sectional shape can be provided and can include a containerhaving a reservoir adapted to receive the biological sample and a liquidcarrier medium, the container being provided with an opening thatcommunicates with the reservoir, a mold having an end and being providedwith a cylindrical bore with a cross sectional shape approximating thecross sectional shape of the at least one bore of the recipient blockand opening at the end of the mold, wherein the end of the mold cansealably engage the opening in the container for permitting thebiological sample and the liquid carrier medium to be transferred fromthe reservoir to the cylindrical bore for forming the core.

The opening in the container can have a cross sectional shape and themold can have an end provided with an outer surface having a crosssectional shape that approximates the cross-sectional shape of theopening in the container. The mold can be configured to slidably andsealably extend into the opening in the container so as to urge thebiological sample and the liquid carrier medium from the reservoir intothe cylindrical bore of the mold. The outer surface of the mold can havea length and the reservoir can have a depth at least equal to the lengthof the outer surface for permitting the end of the mold to slidably andsealably extend into the opening in the container for urging thebiological sample and the liquid carrier medium from the reservoir intothe cylindrical bore of the mold. The assembly can further include aseal provided at the least one of the outer surface of the mold and theopening in the container. The reservoir of the container can be acylindrical bore having a cross sectional shape that approximates thecross-sectional shape of the opening in the container. The assembly canfurther include a plunger slidably disposed in the reservoir for urgingthe biological sample and the liquid carrier medium from the reservoirinto the cylindrical bore of the mold. The assembly can further includea pressurized fluid source coupled to the container for moving theplunger from a first position to a second position for urging thebiological sample and the liquid carrier medium from the reservoir intothe cylindrical bore of the mold. The assembly can further include anactuation element coupled to the plunger for moving the plunger from afirst position to a second position so as to urge the biological sampleand the liquid carrier medium from the reservoir into the cylindricalbore of the mold.

In one aspect of the invention, an assembly for use with biologicalsample material to make a microarray block can be provided and caninclude a cassette having a planar support layer with opposite first andsecond surfaces, the planar support layer being provided with aplurality of openings extending between the first and second surfacesand forming a plurality of support elements in the planar support layer,a recipient block formed from an agarose gel, the recipient block havinga first portion extending from the first surface of the planar supportlayer and a second portion extending from the second surface of theplanar support layer, the recipient block extending through at leastsome of the plurality of openings in the planar support layer so as toembed at least some of the plurality of support elements between thefirst and second portions of the recipient block, the first portion ofthe recipient block having a surface spaced from the first surface ofthe planar support layer and being provided with at least one boreextending from the surface into the first portion that is adapted toreceive the biological sample material.

The at least one bore can include a plurality of parallel boresextending into the first portion. The at least one bore can extend intothe first portion extends through one of the plurality of openings inthe planar support layer and through the second portion. The at leastone bore can have a first section in the first portion with a transversedimension and a second section in the second portion with a transversedimension that is smaller than the transverse dimension of the firstsection. The surface of the first portion can be planar and parallel tothe planar support layer and the second portion can have a surface thatis planar and parallel to the planar support layer. The agarose gel ofthe recipient block can be dehydrated and infiltrated with paraffin.

In one aspect of the invention, a method for forming an assembly for usewith biological sample material to make a microarray block can beprovided and can include providing a cassette having a planar supportlayer with opposite first and second surfaces, the planar support layerbeing provided with a plurality of openings forming a plurality ofsupport elements in the planar support layer and forming a recipientblock from an agarose gel having a first portion extending from thefirst surface of the planar support layer and a second portion extendingfrom the second surface of the planar support layer, the recipient blockextending through at least some of the plurality of openings in theplanar support layer so as to embed at least some of the plurality ofsupport elements between the first and second portions of the recipientblock.

The method can further include the step of forming at least one boreextending into the first portion that is adapted to receive thebiological sample material. The forming step can include providing afirst mold in front of the first surface of the planar support layer andproviding a second mold in front of the second surface of the planarsupport layer and introducing agarose gel into the first and secondmolds to respectively form the first and second portions of therecipient block.

The apparatus and methods of the present invention can offer significantadvantages over the prior art, which are highly relevant to the qualityand quantity of final product achievable from a fixed amount of samplematerial, which in certain instances can be a precious resource. Forexample, the apparatus and methods of the invention can increase theutilization, and thereby reduce the waste, of sample material byreducing the fraction of sample material that is not formed into thedesired shape for the cores of a microarray, enabling extremely largeaspect ratio, that is ratio of length to diameter, in resulting cores ora combination of the foregoing. In this regard, for example, typicalvalues of diameter in tissue/cell microarrays are from 0.5 millimeter to5.0 millimeter, while the apparatus and method of the invention enablesthis range and beyond, for example 0.1 millimeter to 25 millimeters, andwith aspect ratios up to the order of 100. The apparatus and method ofinvention enable microarray block core lengths to be much longer thanconventionally done, and more uniform in length than conventionallydone. In this regard, for example, typical depths of cores, for exampleas shown in FIG. 1, are at most three to five millimeters, while theapparatus and method of the invention permit microarray blocks with coredepths of 20 to 50 millimeters, thus enabling greater efficiencies uponhistologic sectioning.

The apparatus and methods of the invention can facilitate techniques formaximizing the uniformity of the resulting cores. In this regard, avariety of mixing and/or concentrating techniques, for example vortexmixing and centrifugation, are enabled. In addition, minimization of airbubbles introduced to the sample is enabled by the ability of theapparatus and method of the invention to include the application ofvacuum and/or heat for dissolution of gases, centrifugation for bubblesremoval due to buoyancy, inversion of the casting element and containerelement assembly, for example as shown in FIGS. 9-12, just prior tocompletion of the stroke, for example as shown in FIG. 9D, 10D, 11D, or12D, in order to sequester air bubbles from entering the lumen of thecasting element, or any combination of the foregoing.

The apparatus and methods of the invention can facilitate maintainingsterility and purity of the core since the components, for example thecasting element and container element for example as shown in FIGS.9-12, can be simple, disposable components.

We claim:
 1. A method for making a microarray block, comprising:providing a mold having a cylindrical bore, the mold having oppositefirst and second ends, the first end of the mold having an opening ofthe cylindrical bore, introducing a biological sample and a liquidcarrier medium of the aqueous form of an agarose gel through the openingin the mold, the biological sample being selected from the groupconsisting of a tissue sample, cell cultures and a combination of theforegoing, solidifying the liquid carrier medium in the mold to form acylindrical core formed of both the biological sample and the agarosegel and having a length, the biological material being distributed alongthe length of the cylindrical core, removing the cylindrical core fromthe mold, disposing at least a portion of the cylindrical core in aninternal bore in a recipient block formed from a material selected fromthe group consisting of paraffin wax, an agarose gel and a combinationof the foregoing, and dehydrating the cylindrical core and infiltratingthe cylindrical core with paraffin before the disposing step to make thecylindrical core capable of forming a bond with the recipient block ofsufficient strength to enable sections with physical integrity to be cutfrom the recipient block for analysis.
 2. The method of claim 1, whereinthe recipient block is formed from paraffin.
 3. The method of claim 1,wherein the internal bore has a length and the cylindrical core has alength that is greater than the length of the internal bore.
 4. A methodfor making a microarray block, comprising: providing a cylindrical coreformed of both a biological sample and an agarose gel and having alength, the biological sample being selected from the group consistingof a tissue sample, cell cultures and any combination of the foregoingand being distributed along the length of the cylindrical core,dehydrating the cylindrical core and infiltrating the cylindrical corewith paraffin to form a processed cylindrical core capable of forming abond with a recipient block of sufficient strength to enable sectionswith physical integrity to be cut from the recipient block for analysis,and disposing at least a portion of the processed cylindrical core in aninternal bore in the recipient block formed from a material selectedfrom the group consisting of paraffin wax, an agarose gel and acombination of the foregoing.
 5. The method of claim 4, wherein theinternal bore of the recipient block has a cross-sectional shape, thecylindrical core having a cross-sectional shape equal to thecross-sectional shape of the internal bore.
 6. The method of claim 4,wherein the internal bore in the recipient block has a length and thecylindrical core has a length that is greater than the length of theinternal bore.
 7. The method of claim 4 wherein the recipient block hasa plurality of internal bores and wherein the disposing step includesdisposing at least a portion of the processed cylindrical core into theplurality of internal bores.
 8. The method of claim 7, furthercomprising slicing the recipient block into a plurality of sections eachcontaining a plurality of sections of the processed cylindrical core. 9.The method of claim 4, wherein the processed cylindrical core is one ofa plurality of processed cylindrical cores formed via the method ofclaim 4, wherein the recipient block has a plurality of internal boresand wherein the disposing step includes disposing at least a portion ofone of the plurality of processed cylindrical cores into each of theplurality of internal bores.
 10. The method of claim 4, wherein thecylindrical core has a diameter ranging from 0.1 millimeter to 25millimeters.
 11. The method of claim 4, wherein the cylindrical core hasa length and a transverse dimension and a ratio of length to transversedimension of up to the order of
 100. 12. The method of claim 4, whereinthe internal bore of the recipient block has a cross sectional shape,further comprising the steps of: providing a mold having a cylindricalbore with a cross sectional shape equal to the cross sectional shape ofthe internal bore, the mold having opposite first and second ends, thefirst end of the mold having an opening of the cylindrical bore of themold, introducing the biological sample and a liquid carrier medium ofthe aqueous form of the agarose gel through the opening, solidifying theliquid carrier medium of the aqueous form of the agarose gel in the moldto form the cylindrical core of both the biological sample and theagarose gel, and removing the cylindrical core from the mold.
 13. Themethod of claim 12, further comprising the step of mixing the biologicalsample and the liquid carrier medium of the aqueous form of the agarosegel within the cylindrical bore of the mold.
 14. The method of claim 12,further comprising the step of mixing the biological sample and theliquid carrier medium of the aqueous form of the agarose gel before theintroducing step.
 15. The method of claim 12, wherein the solidifyingstep comprises heating the biological sample and the liquid carriermedium of the aqueous form of the agarose gel in the mold.
 16. Themethod of claim 12, wherein the internal bore in the recipient block hasa length and the cylindrical core has a length that is greater than thelength of the internal bore.
 17. The method of claim 4, furthercomprising the steps of: providing a mold having a cylindrical bore, themold having opposite first and second ends, the first end of the moldhaving an opening of the cylindrical bore, introducing the biologicalsample and a liquid carrier medium of the aqueous form of the agarosegel through the opening in the mold, solidifying the biological sampleand the liquid carrier medium of the aqueous form of the agarose gel inthe mold to form the cylindrical core of both the biological sample andthe agarose gel, and removing the cylindrical core from the mold.